Artikel ; Online: Blocking soluble TNFα sensitizes HER2-positive breast cancer to trastuzumab through MUC4 downregulation and subverts immunosuppression.
Journal for immunotherapy of cancer
2023 Band 11, Heft 3
Abstract: Background: The success of HER2-positive (HER2+) breast cancer treatment with trastuzumab, an antibody that targets HER2, relies on immune response. We demonstrated that TNFα induces mucin 4 (MUC4) expression, which shields the trastuzumab epitope on ... ...
| Abstract | Background: The success of HER2-positive (HER2+) breast cancer treatment with trastuzumab, an antibody that targets HER2, relies on immune response. We demonstrated that TNFα induces mucin 4 (MUC4) expression, which shields the trastuzumab epitope on the HER2 molecule decreasing its therapeutic effect. Here, we used mouse models and samples from HER2+ breast cancer patients to unravel MUC4 participation in hindering trastuzumab effect by fostering immune evasion. Methods: We used a dominant negative TNFα inhibitor (DN) selective for soluble TNFα (sTNFα) together with trastuzumab. Preclinical experiments were performed using two models of conditionally MUC4-silenced tumors to characterize the immune cell infiltration. A cohort of 91 patients treated with trastuzumab was used to correlate tumor MUC4 with tumor-infiltrating lymphocytes. Results: In mice bearing de novo trastuzumab-resistant HER2+ breast tumors, neutralizing sTNFα with DN induced MUC4 downregulation. Using the conditionally MUC4-silenced tumor models, the antitumor effect of trastuzumab was reinstated and the addition of TNFα-blocking agents did not further decrease tumor burden. DN administration with trastuzumab modifies the immunosuppressive tumor milieu through M1-like phenotype macrophage polarization and NK cells degranulation. Depletion experiments revealed a cross-talk between macrophages and NK cells necessary for trastuzumab antitumor effect. In addition, tumor cells treated with DN are more susceptible to trastuzumab-dependent cellular phagocytosis. Finally, MUC4 expression in HER2+ breast cancer is associated with immune desert tumors. Conclusions: These findings provide rationale to pursue sTNFα blockade combined with trastuzumab or trastuzumab drug conjugates for MUC4+ and HER2+ breast cancer patients to overcome trastuzumab resistance. |
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| Mesh-Begriff(e) | Mice ; Animals ; Trastuzumab/pharmacology ; Trastuzumab/therapeutic use ; Down-Regulation ; Mucin-4/genetics ; Mucin-4/metabolism ; Tumor Necrosis Factor-alpha/metabolism ; Receptor, ErbB-2 ; Cell Line, Tumor ; Immunosuppression Therapy ; Neoplasms/drug therapy |
| Chemische Substanzen | Trastuzumab (P188ANX8CK) ; Mucin-4 ; Tumor Necrosis Factor-alpha ; Receptor, ErbB-2 (EC 2.7.10.1) |
| Sprache | Englisch |
| Erscheinungsdatum | 2023-03-08 |
| Erscheinungsland | England |
| Dokumenttyp | Journal Article ; Research Support, Non-U.S. Gov't |
| ZDB-ID | 2719863-7 |
| ISSN | 2051-1426 ; 2051-1426 |
| ISSN (online) | 2051-1426 |
| ISSN | 2051-1426 |
| DOI | 10.1136/jitc-2022-005325 |
| Datenquelle | MEDical Literature Analysis and Retrieval System OnLINE |
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